Careful study of genes responsible for rare mendelian forms of human neurological disorders is a powerful approach for gaining insight into the causes, treatment, and potential cure for common, related diseases. The neuronal KCNQ genes were recently discovered as the result of the search for mutant genes causing Benign Familial Neonatal Convulsions, an autosomal dominant epileptic syndrome associated with seizures in infancy and throughout life. Mutations in neuronal KCNQ genes also result in myokymia (a peripheral nerve disorder) and deafness. The KCNQ genes encode subunits of voltage-dependent potassium channels The long term goals of the proposed work is to understand the in vivo functions of these neuronal KCNQ channels, in order to better understand basic brain signaling mechanisms and to exploit these mechanisms for neurological therapeutics. KCNQ channels regulate neuronal excitability through their intrinsic, voltage-gated activity at particular locations in brain, and through their ability to serve as effectors for neurotransmitter receptors and intracellular signaling pathways. Determining specifically where KCNQ channels are localized in brain circuits, and how receptors and pathways modulate their activity in the brain, will enhance our ability to exploit M-channels as therapeutic targets in conditions involving excessive excitability or alterations and imbalances in modulatory neurotransmission, such as epilepsy, pain syndromes, and Alzheimer's disease. The current proposal focuses on particular brain circuits in the septum and hippocampus, and particular presynaptic and post-synaptic localizations, where previous work by the investigator and others indicates KCNQ channels play important roles. The specific aims are to: (1) map the localization of KCNQ subunits in mammalian septohippocampal networks in developing and mature brain; (2) define the mechanisms of targeting and stabilization of KCNQ2 subunits at axon initial segments and nodes of Ranvier in brain, spinal cord, and peripheral nerve; and (3) analyze the localization and function of KCNQ channels in lines of mutant mice that exhibit hyperexcitability and epilepsy due to expression of a dominant-negative mutant of the KCNQ2 subunit. [unreadable] [unreadable]